The overall objective of the proposed research is to characterize viral and cellular popuations in the lymphatic tissue (LT) niche to better understand HIV pathogenesis and improve treatment based on that knowledge. The proposed research continues to focus on the roles of infected resting and activated CD4+ T cells in the transmission, propagation and persistence of infection and the generation of latently infected cells that cannot be eradicated by current treatment. Additionally, the role and mechanism by which fibrosis impairs the ability of the LT niche to sustain and reconstitute CD4+ T cell populations will be investigated. In situ hybridization and PCR, histochemical and immunohistochemical staining, a new method to visualize virion production in tissues and quantitative image analysis will be used to characterize virus production by resting and activated T cells; relationship of infection of these cells and macrophages to their population densities in LTs; relationship of minimally productively infected cells to emergence of latently infected cells; and relationship of collagen in LTs to restoration of CD4+ T cell populations with treatment.